AML is a clonal disorder clinically presenting as increased proliferation of heterogeneous and undifferentiated myeloid blasts. Understanding the biology of human AML stem/progenitor cells is an important prerequisite for the development of more efficacious therapeutic strategies in the treatment of AML as current therapies fail to permanently eradicate the disease in a significant proportion of patients (Patel, J., et al. The New England Journal of Medicine 366, 1079-1089 (2012)). Studies by Lapidot and Dick (Lapidot, T., et al. Nature 367, 645-648 (1994)) are at the basis of the current understanding of AML as a heterogeneous disease consisting of cells which differ from each other with regards to proliferative potential, cell cycle kinetics, resistance to chemotherapy and self-renewal capacity thus caricaturing the hierarchy of the normal hematopoietic system (Bonnet, D. & Dick, J. Nature medicine 3, 730-737 (1997); Hope, K., Jin, L. & Dick, J. Nature immunology 5, 738-743 (2004); Ishikawa, F., et al. Nature biotechnology 25, 1315-1321 (2007); Pearce, D., et al. Blood 107, 1166-1173 (2006)). Leukemia initiating cells (LIC) which are defined by their potential to engraft immunocompromised mice are at the apex of this hierarchy and share some important features with normal hematopoietic stem cells (HSC) as the ability to self-renew and to recapitulate the diversity of the hierarchy. Engraftment potential of human leukemic cells in immunocompromised mice has been correlated with clinical outcome in adult (Pearce D. et al., supra) and more recently pediatric leukemia patients (Woiterski, J., et al. International journal of cancer March 23. doi: 10.1002/ijc.28170. [Epub ahead of print] (2013)). Furthermore, leukemic stem cell associated gene expression signatures (Eppert, K., et al. Nature medicine 17, 1086-1093 (2011); Gentles, A., Plevritis, S., Majeti, R. & Alizadeh, A. JAMA: the journal of the American Medical Association 304, 2706-2715 (2010)) identified by comparative microarray studies have been associated with worse survival providing evidence for clinical relevance of these experimentally defined cells. However, LICs rapidly differentiate or/and undergo apoptosis when deprived of their in vivo environment and exposed to currently available in vitro conditions, which is a major obstacle in the development of LIC targeted therapies and casts doubt on the interpretation of results emanating from ex vivo treatment of these cells. Cell lines which have been used in the past for drug screenings have overcome these constraints but do not reflect the hierarchical organization of the primary disease anymore which makes them an inappropriate tool for the development of LIC targeted therapies.
There is thus a need for strategies to modulate AML stem/progenitor cell expansion and/or differentiation.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.